This application is the National Stage of International Application No. PCT/JP98/01870, filed Apr. 23, 1998.
The present invention provides an apatite-coated solid composition containing a biodegradable polymer, an apatite-coated solid composition containing a biodegradable polymer and a medicinal substance, and a method for producing the solid composition.
The bone and teeth of vertebrates are composed of 70% of a mineral phase and 30% of an organic matrix, with the constitution of the mineral phase closely resembling that of hydroxyapatite. Therefore, investigations into the possible utilization of apatite as a biological material began around 1970. As substitutes for bone, metallic materials such as stainless steel, cobalt-chromium alloy, titanium alloys, etc. and organic compounds such as high density polyethylene, polymethyl methacrylate, etc. had been used for some time. However, since those materials are incapable of being fused directly to the bone tissue, loosening and breakage of the implants occur with a high incidence, inducing adverse responses such as chronic inflammation of the surrounding tissue. To secure a firmer fusion to bone, a technology comprising coating the surface of such a material with hydroxyapatite by, for example, sputtering or plasma spray coating has been developed and is in practice.
Various contrivances were made for securing a firm fusion of biochemical materials to bone, and it was discovered that when SiO2xe2x80x94Na2Oxe2x80x94CaOxe2x80x94P2O5 type glass is implanted in bone, an intimate chemical coupling takes place. Further improvements led to the development of an alkali metals-free glass ceramic comprising apatite and wollastonite crystals (the Axe2x80x94W glass ceramic) starting with a powder of SiO2xe2x80x94CaOxe2x80x94P2O5xe2x80x94MgOxe2x80x94CaF2 glass via sintering and crystallization. The research into the mechanism of fusion of this material to bone is well-documented and in view of its high mechanical strength, this material has been clinically applied with success as bone graft substitutes for iliac bone and vertebrae.
It was confirmed that between the Axe2x80x94W glass ceramic and bone, there exists a layer of fine poorly oriented apatite crystals formed from the ions released from the Axe2x80x94W glass ceramic and the body fluid components, so that the bone and the implant are intimately bound through this layer. The mechanisms of formation of such an apatite layer have been analyzed using a buffer solution called xe2x80x9csimulated body fluidxe2x80x9d (SBF) which is free of high molecular components such as proteins and has been prepared to match the body fluid only in the concentrations of ions (Manual of Materials for Orthopaedic Materials, Kanehara and Co., Ltd.). It is reported that by taking advantage of such properties of the Axe2x80x94W glass ceramic, an apatite layer could be formed on an organic polymer such as poly(ethylene terephthalate) by immersing the polymer and Axe2x80x94W glass ceramic together in a simulated body fluid (Journal of Biomedical Materials Research, 29, 349-357, 1995). In connection with this technology, it has been recommended that the surface of the polymer be pretreated by glow discharge.
Regarding the exploitation of biodegradable-absorbable polymers in the development of injectable bone substitutes, it has been reported that in an implantation experiment, new bone formation took place in line with the degradation and absorption of a polylactic acid (PLA)-hydroxyapatite (HA) complex, suggesting the possibility of clinical application of such polymers as bone implants (Collection of Papers on Polymers, 42 (11), 771-776, 1985).
Bone remodelling has been confirmed with an implant material comprising either PLA or poly (DL-lactide-co-glycolide) (PLGA) as a carrier and an osteoinductive factor (bone morphogenetic protein, BMP) or a material comprising a complex of said polymer and hydroxyapatite as a carrier and BMP (Abstract of Lectures at the 24th Medical Polymer Symposium, pages 65-66).
Furthermore, it has been reported that in an experiment involving the implantation of a PLA-polyethylene glycol (PEG) block copolymer-BMP complex or a ternary complex containing hydroxyapatite in addition to the above combination at sites of osseous defect they regenerate bone tissues (Clinical Orthopaedics and Related Research, No. 294, pp. 333-343, 1993), thus suggesting their clinical applicability as bone implants.
Powders containing pharmacologically active substances having an activity of promoting bone formation are useful for the therapy of various diseases of bone (e.g. osteoporosis and bone fracture) by injecting or implanting the powder containing such a pharmacologically active substance. Furthermore, applicability of such powders can be expanded in scope and the effect improved by adding new functions such as sustained release and biodegradability to such powders. Meanwhile, it is known that apatite is composed of calcium phosphate just as is bone, thus having a very high affinity for bone and that, therefore, when administered to a host body, apatite does not induce foreign-body reactions such as immune responses, thus being of great utility. However, pharmacologically active substances and powder materials are generally incapable of withstanding the tortuous conditions of sputtering, plasma spray coating, and other coating operations but undergo degradation in their course.
The inventors of the present invention thought it possible to effectively exploit the pharmacologic action of a powder containing a drug substance by covering the surface of the powder with apatite and did intensive investigations. As a result, they found that when a powder is immersed in an aqueous solution containing various ions, an apatite coating layer is formed on the surface of the particles with good efficiency under mild conditions. The finding was followed by further research which has culminated in the present invention.
The present invention is:
(1) An apatite-coated solid composition containing a biodegradable polymer,
(2) A solid composition according to item (1), which contains a medicinal substance,
(3) A solid composition according to item (2), which comprises a sustained release preparation,
(4) A solid composition according to item (1), wherein the biodegradable polymer is polylactic acid, polyglycolic acid, or a copolymer of polylactic acid and polyglycolic acid,
(5) A solid composition according to item (2), wherein the medicinal substance is hardly soluble in water,
(6) A solid composition according to item (2), wherein the medicinal substance is a medicine for prophylaxis or treatment of bone diseases, an antibiotic, an anti-inflammatory agent or an anti-tumor agent,
(7) A solid composition according to item (1), wherein the apatite is a crystalline mineral substance which has (1) at least one cation selected from the group consisting of Na+, K+, H+, Ca2+, Sr2+, Ba2+, Pb2+, Zn2+, Cd2+, Mg2+, Fe2+, Mn2+, Ra2+, Al3+, Y3+, Ce3+, Nd3+, La3+ and Dy3+, and (2) at least one anion selected from the group consisting of SO42xe2x88x92, CO32xe2x88x92, HPO42xe2x88x92, PO3F2xe2x88x92, PO43xe2x88x92, AsO43xe2x88x92, VO43xe2x88x92, BO33xe2x88x92, CrO43xe2x88x92, SiO43xe2x88x92, GeO43xe2x88x92, (CO3F)3xe2x88x92 and BO45xe2x88x92,
(8) A solid composition according to item (1), wherein the apatite is hydroxyapatite,
(9) A solid composition according to item (1), wherein the apatite is phosphate apatite,
(10) A solid composition according to item (1), which is in a microcapsule preparation,
(11) A solid composition according to item (1), wherein the apatite layer has a honeycomb structure,
(12) A solid composition according to item (1), wherein the apatite layer is about 1 nm to 50 xcexcm,
(13) A method for producing an apatite-coated solid composition containing a biodegradable polymer, which comprises subjecting a substrate of a solid composition containing a biodegradable polymer to immersion in an aqueous ion solution which is capable of forming an apatite,
(14) A method according to item (13), wherein the solid composition contains a medicinal substance,
(15) A method according to item (13), wherein the aquoeus ion solution is an aqueous solution which contains at least one of Na+, K+, Mg2+, Ca2+, Clxe2x88x92, CO32xe2x88x92, PO43xe2x88x92 and SO42xe2x88x92, and (16) A method according to item (13), wherein the temperature at the immersion is about 10 to 150xc2x0 C.
The present invention also provides an apatite-coated solid composition containing (1) a biodegradable polymer or (2) a biodegradable polymer and a medicinal substance, which is formed by immersing a substrate of a solid composition containing (1) a biodegradable polymer or (2) a biodegradable polymer and a medicinal substance in an aqueous ion solution which is capable of forming an apatite.